Page 81 - Medicinal Chemistry Self Assessment

70 Medicinal Chemistry Self Assessment

3. The sodium salt of montelukast is required for its oral administration, whereas zafirlukast can be
administered orally as its unionized free acid form. Conduct a structural analysis of these two drug
molecules and provide an explanation for this difference.

4. Montelukast and zafirlukast exert their mechanism of action by interacting with cysteinyl leukotriene
Montelukast
receptors and blocking the normal actions of endogenous leukotrienes (LTC , LTD , and LTE ). It has
4
4
4
been proposed that this interaction requires five key elements: an ionic interaction, a hydrogen bond
interaction where the antagonist acts as the acceptor, as well as the interaction of the antagonist
with three separate hydrophobic pockets within the receptor. Using this information and the struc-
tures of montelukast and zafirlukast, propose potential binding interactions between these drug
molecules and cysteinyl leukotriene receptors. Assume that all binding interactions occur at a physi-
ological pH=7.4. Zafirlukast

5. Calculated log P values of montelukast and zafirlukast lie in the range of 5.5 to 6.4 depending on the
computer program used to predict these values. Given this information, would these drug molecules
be predicted to be highly plasma protein bound or minimally plasma protein bound? Additionally,
1. The structure of
would you expect these drug molecules to undergo extensive hepatic metabolism or be primarily
2. In the use the Rule of Nines to calculate the percent of the functional group that would be ionized.
excreted unchanged?
3. The an explanation for this difference.
4. Montelukast and zafirlukast. Assume that all binding interactions occur at a physiological pH of 7.4.
6. Shown below is the structure of zafirlukast and a list of five metabolic transformations. For each
metabolic transformation, indicate if it is a phase I or a phase II transformation and if zafirlukast has
5. Calculated log P these hepatic metabolism or be primarily excreted unchanged?
a functional group present that can participate in the transformation. If you answer YES, then draw
6. Shown below is to perform with zafirlukast.
the appropriate metabolite; if you answer NO, then provide a brief explanation as to why this meta-
bolic transformation is not possible to perform with zafirlukast.
Metabolic Pathways
A. Methylation

B. Aromatic Oxidation
C. Hydrolysis

D. Oxidative O-Dealkylation
E. Benzylic Oxidation